The present invention was made with the support of the National Institutes of Health under Grant No. ROI CA 34619. The Government has certain rights in the invention.
Cyclophosphamide (also known as cytoxan) (I) is one of the most widely used anti-cancer drugs. ##STR2## It is generally administered in combination with a number of other drugs to treat a wide variety of hematologic and solid tumors. However, there are several features of the drug that limit its clinical utility. First, the drug requires activation in the liver to produce metabolites that are toxic to cancer cells. Second, the drug is specifically toxic to the urinary bladder and also displays the bone marrow toxicity typical of the alkylating agent class of anti-cancer drugs. Third, cyclophosphamide is a potent suppressor of the immune system at the doses used to treat cancer, thus decreasing the infection-fighting ability of patients already debilitated by their disease. Finally, repeated use of cyclophosphamide frequently results in the development of resistance to the drug by a patient's cancer cells, thus rendering the drug ineffective.
In an attempt to circumvent at least some of these disadvantages, a number of analogs have been disclosed, which preserve at least some of the structural features of cyclophosphamide. For example, published PCT application WO 89/11484, by Research Corporation Technologies, Inc. discloses phosphoramides of the general formula: ##STR3## wherein R.sub.1 and R.sub.2 may be H or haloalkyl, R may be a nitrosubstituted heteroaromatic group and R.sub.3 and R.sub.4 may independently be hydrogen, (C.sub.1 -C.sub.10)alkyl or an electron-withdrawing group, such as CO.sub.2 Et. Although these compounds are disclosed to be desirably cytotoxic in hypoxic cells, the most active compounds disclosed comprise at least one electronwithdrawing group at R.sub.3 or R.sub.4, which necessarily complicates their synthesis and reduces their stability. See also, Borch et al. (U.S. Pat. Nos. 4,908,356 and 5,190,929).
Therefore, a continuing need exists for cyclophosphamide analogs which are highly cytotoxic against a wide variety of tumor cells, while being stable and easy to prepare.